The present invention provides processes and intermediates useful in the preparation of certain xcex23-adrenergic receptor agonists, which agonists are useful in treating, inter alia, hypoglycemia, and obesity, and for increasing the content of lean meat in edible animals.
Diabetes mellitus is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The results of these defects include, inter alia, elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs, and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin, the hormone that regulates carbohydrate utilization. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated, levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most Type 2 diabetic patients are also obese.
Obesity constitutes a major health risk that leads to mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia. In the United States, more than 50% of the adult population is overweight, and almost 25% of the population is considered to be obese. The incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. Furthermore, obesity is a devastating disease which can also wreak havoc on an individual""s mental health and self-esteem, which can ultimately affect a person""s ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on society in general, much effort has been expended in efforts to treat obesity, however, success in the long-term treatment and/or prevention thereof remains elusive.
In response thereto, a diversity of therapeutic agents have been developed including, for example, xcex23-adrenergic receptor activators/agonists. Activation of xcex23-adrenergic receptors is known to stimulate lipolysis (e.g., the breakdown of adipose tissue triglycerides into glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting the loss of fat mass. Accordingly, compounds that stimulate xcex23-adrenergic receptors are useful as anti-obesity agents. In addition, compounds that are xcex23-adrenergic receptor agonists have hypoglycemic activity, however, the precise mechanism of this effect is presently unknown.
Commonly assigned U.S. Provisional Application No. 60/242,274, filed Oct. 20, 2000, and incorporated herein by reference, discloses certain xcex23-adrenergic receptor agonists of the general structural Formula (I), 
the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs.
The instant invention provides processes useful in the preparation of certain xcex23-adrenergic receptor agonists of structural Formula (I), which agonists are disclosed in detail hereinbelow. The invention further provides intermediates useful in the preparation of such agonists, and processes useful in the production of such intermediates.
The present invention provides processes useful in the preparation of certain xcex23-adrenergic receptor agonists of the structural formula 
the pharmaceutically acceptable salts thereof, and the hydrates of said pharmaceutically acceptable salts, wherein HET is as defined hereinbelow. The invention further provides intermediates useful in the preparation of such agonists, and processes useful in the production of such intermediates.
The present invention provides processes useful in the preparation of certain xcex23-adrenergic receptor agonists of the structural formula 
the pharmaceutically acceptable salts thereof, and the hydrates of said pharmaceutically acceptable salts, wherein HET is a heterocyclic moiety selected from the group consisting of oxazolyl, pyrazolyl, and thiazolyl.
The invention further provides intermediates useful in the preparation of such agonists, and processes useful in the production of such intermediates. These enantioselective processes, to be described in greater detail hereinbelow, proceed in a convergent manner, utilize a minimum number of starting materials, and furnish products retaining an overall high degree of enantiospecificity.
In one aspect of the present invention, there is provided a process for preparing a compound of the structural formula 
a pharmaceutically acceptable salt thereof, or a hydrate of said pharmaceutically acceptable salt, which process comprises the steps of:
(a) reducing an xcex1-bromoketone derivative of the structural formula 
or an acid addition salt thereof, to form an (R)-bromoalcohol derivative of the structural formula 
(b) protecting the (R)-bromoalcohol derivative of Step (a) to form an O-protected derivative of the structural formula 
(c) condensing the O-protected derivative of Step (b) with an amine of the structural formula 
to produce an O-protected derivative of the structural formula 
(d) deprotecting the O-protected derivative of Step (c) to form the compound of the structural formula 
wherein:
HET is a heterocyclic moiety selected from the group consisting of oxazolyl, pyrazolyl, and thiazolyl; and
P is an O-protecting moiety selected from the group consisting of xe2x80x94SiR1R2R3, xe2x80x94CH2Ph, xe2x80x94CH2(p-CH3OPh), xe2x80x94CH(OCH2CH3)CH3, and 
wherein R1, R2, and R3 are, independently, (C1-C6)alkyl, or phenyl.
Preferably, P is xe2x80x94SiR1R2R3, and HET is a heterocyclic moiety selected from the group consisting of 2-oxazolyl, 4-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, and 4-thiazolyl. The process wherein P represents xe2x80x94SiR1R2R3, wherein R1 and R2 are both xe2x80x94CH3, and R3 is xe2x80x94C(CH3)3 is especially preferred.
The stereospecific reduction step, denoted hereinabove as Step (a), preferably employs a fungal reducing agent. Generally, the use of fungal and/or microbial reducing agents in the stereospecific biotransformation of pharmaceutical intermediates is known. See, for example, R. N. Patel, Advances in Applied Microbiology, 43, 91-140 (1997). Specifically, the stereospecific reduction of xcex1-haloketones with various microorganisms is also generally known. See, for example, R. N. Patel, et al., JAOCS, 75 (11), 1473-1482 (1998), which discloses the use of Agrobacterium tumefaciens ATCC 15955, Alcaligenes eutrophus ATCC 17697, Arthrobacter petroleophagus ATCC 21494, Debaryomyces hansenil ATCC 66354, Mycobacterium sp. ATCC 29676, Rhodococcus rhodochorous ATCC 14347, Hansenula anomala SC 13833, H. anomala ATCC 16142, H. saturnus SC 13829, and Spingomonas paucimobilis SC 16113 in the stereospecific reduction of xcex1-bromoketones. The fungal reducing agent utilized in reduction Step (a) of the instant invention preferably comprises Absidia cylindrospora ATCC 22751 (American Type Culture Collection, Rockville, Md.). The aforementioned reduction step affords the corresponding (R)-bromoalcohol in a highly enantioselective yield, i.e.  greater than 90% enantiomeric excess. Preferably, the (R)-bromoalcohol so formed in the stereospecific reduction Step (a) is then isolated, either as a free base, or an acid addition salt thereof.
The (R)-bromoalcohol product formed in the stereospecific reduction Step (a) is then O-protected. Synthetic methods of protecting alcohol functional groups are well-known to one of ordinary skill in the art and may comprise, for example, functionalizing the alcohol as a silyl, ether, or ester derivative thereof. Although any conventional O-protecting group that is compatible with the reaction conditions employed in subsequent synthetic steps may be employed in the processes of the present invention, the (R)-bromoalcohol product of Step (a) is preferably protected as an O-silyl ether derivative. The preferred O-silylation step, generically denoted hereinabove as Step (b), may be effected according to standard methodologies that will be known to one of ordinary skill in the art. Such preferred O-silylation is typically effected by treatment of the (R)-bromoalcohol with an appropriately substituted silylating agent. Such silylating agents may comprise, for example, those silyl derivatives of the formula R1R2R3Sixe2x80x94X, wherein X comprises an appropriate leaving group. Preferably, the silylating agent comprises a reactant of the formula R1R2R3Sixe2x80x94X, wherein X is a leaving group selected from the group consisting of halogen (e.g., chloro or bromo), cyano, imidazolyl, triflate (trifluoromethanesulfonate), and the like. However, other silylating agents, that may be employed in accordance with the processes of the instant invention, will also be known to one of ordinary skill in the art. Preferably R1, R2, and R3, within the definition of the protected alcohol moiety xe2x80x94OSiR1R2R3 are, independently, (C1-C6)alkyl, or phenyl. The O-silyl ether derivative wherein R1 and R2 are both xe2x80x94CH3, and R3 is xe2x80x94C(CH3)3 is especially preferred.
Typically, O-silylation is effected by condensing the alcohol to be protected with the silylating agent in the presence of a suitable organic base, for example, an alkylamine, such as triethylamine, N,N-diisopropylethylamine (Hunig""s base), or a heterocyclic amine, such as imidazole or diazabicyclo[5.4.0]undec-7-ene (DBU), in a halogenated hydrocarbon solvent, such as dichloromethane. Alternatively, a polar, aprotic solvent, such as dimethylformamide or dimethylsulfoxide may also be employed. With respect to the O-silylation reaction of the present invention, dimethylformamide is preferred. Typically, such silylation is effected by stirring the reactants at, or about, room temperature for an extended period of time, i.e., overnight. However, such silylation may also be performed at greater, or lesser, than ambient temperature, where appropriate.
For a detailed discussion of methods of protecting alcohol functional groups, including those preferred methods employing silylating agents see, for example, T. W. Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, New York, N.Y. (1991), and the references cited therein.
The O-protected derivative so formed in Step (b) is then condensed in Step (c) with an amine of the structural formula 
wherein HET is as defined hereinabove, to provide a product of the structural formula 
The aforementioned condensation Step (c) may be carried out under standard reaction conditions known to one of ordinary skill in the art. Preferably, the protected (R)-bromoalcohol and the amine are condensed in the presence of a suitable organic base, for example, an alkylamine, such as triethylamine or N,N-diisopropylethylamine (Hunig""s base), in a polar, aprotic solvent, such as dimethylsulfoxide. Such condensation is typically effected at an elevated temperature, preferably in the general range of from about 40xc2x0 to about 120 C. Preferably R1, R2, and R3, within the definition of the preferred moiety xe2x80x94SiR1R2R3 are, independently, (C1-C6)alkyl, or phenyl. The process where R1 and R2 are both xe2x80x94CH3, and R3 is xe2x80x94C(CH3)3 is especially preferred. The amines employed in condensation Step (c) may be prepared according to the exemplary processes to be described in detail hereinbelow.
The deprotection step, denoted hereinabove as Step (d), may be performed according to standard methods that will be known to one of ordinary skill in the art. The preferred xe2x80x94Oxe2x80x94SiR1R2R3 derivative formed in Step (c) is preferably deprotected by the reaction thereof with a suitable alkylammonium fluoride, such as tetrabutylammonium fluoride. Such deprotection may be effected at ambient temperature in an aprotic solvent, for example, tetrahydrofuran. For a detailed discussion of methods of deprotecting O-silyl ethers see, for example, T. W. Greene, et al., supra, and the references cited therein.
The deprotected product of Step (d) is then preferably isolated, either in the form of the free base or, if desired, in the form of a pharmaceutically acceptable salt, or a hydrate of such pharmaceutically acceptable salt. Such isolation may be effected according to well-established methods. Likewise, the pharmaceutically acceptable salt may also be prepared according to known methods including, for example, treatment of the isolated free base with a conjugate organic acid, such as succinic, tartaric, acetic, citric, maleic, methanesulfonic, or p-toluenesulfonic acid, and the like. Alternatively, a conjugate inorganic acid, such as hydrochloric, hydrobromic, sulfuric, or nitric acid, and the like, may also be employed. The tosylate salt, i.e., the p-toluenesulfonic acid salt, abbreviated in the instant description and appendant claims as TsOH, of the deprotected product formed in Step (d) is especially preferred. For purposes of facilitating product isolation and augmenting purity, such salt formation is preferably carried out in a reaction-inert solvent, for example, a non-solvent from which the desired salt precipitates upon formation, or, more preferably, in a solvent from which the formed salt precipitates upon subsequent addition of a non-solvent.
One of ordinary skill in the art will further appreciate that such pharmaceutically acceptable salts may form various hydrated forms thereof, and such hydrated forms are embraced within the scope of the present invention. Hydrates of pharmaceutically acceptable salts may be prepared according to well-known methods including, for example, sublimation, crystallization of the hydrate from a single solvent, formation of the hydrate by evaporation from a binary mixture, vapor diffusion, thermal treatment, and the like. For a detailed discussion of methods of preparing hydrates of pharmaceutically acceptable salts see, for example, J. Keith Guillory, Polymorphism in Pharmaceutical Solids, Chapter 5, xe2x80x9cGeneration of Polymorphs, Hydrates, Solvates, and Amorphous Solidsxe2x80x9d, pp. 183-219, Marcel Dekker, Inc. (1999).
In another aspect, the instant invention provides a process for preparing a compound of the structural formula 
or an acid addition salt thereof, which process comprises the steps of:
(a) functionalizing a compound of the structural formula 
to provide a compound of the structural formula 
(b) defunctionalizing the compound so formed in Step (a) to provide the compound of the structural formula 
wherein:
HET is a heterocyclic moiety selected from the group consisting of oxazolyl, pyrazolyl, and thiazolyl.
Preferably, HET represents a heterocyclic moiety selected from the group consisting of 2-oxazolyl, 4-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, and 4-thiazolyl.
In the functionalization step, denoted as Step (a) hereinabove, a phenolic compound of the structural formula 
is functionalized to provide a carbamate of the structural formula 
Such phenolic compounds, which may be prepared according to literature methods or, alternatively, according to the synthetic procedures disclosed hereinbelow, are most conveniently functionalized in Step (a) by the reaction thereof with a compound having the general formula PhCH2OCONHCH2CH2xe2x80x94Y, wherein Y comprises an appropriate leaving group. Exemplary leaving groups comprise those selected from the group consisting of tosylate (p-toluenesulfonate), mesylate (methanesulfonate), halogen (e.g., bromo, chloro, or iodo), and the like. A mesylate leaving group is generally preferred. The compound of the general formula PhCH2OCONHCH2CH2xe2x80x94Y, wherein Y is mesylate may be prepared as disclosed in C. A. Townsend, et al., Tetrahedron 47, 2591 (1991). Functionalization of the phenolic compound is preferably effected in a polar, aprotic solvent, such as dimethylsulfoxide, in the presence of an inorganic base, such as potassium carbonate. The functionalization is typically effected at an elevated temperature, generally in the general range of from about 40xc2x0 to about 120xc2x0 C.
The carbamate derivative so formed in functionalization Step (a) hereinabove is then defunctionalized in Step (b) to provide a compound of the structural formula 
Such defunctionalization of the carbamate product formed in Step (a) may be carried out according to established methods. For example, the carbamate may be defunctionalized by catalytic hydrogenation employing a suitable metallic catalyst, such as a nickel salt, or a complex thereof, a palladium salt, or a complex thereof, or platinum, or a complex thereof. Preferably, the defunctionalization is effected in a polar, protic solvent, such as methanol, using ammonium formate and formic acid in the presence of a metallic catalyst, preferably, palladium on activated carbon. Such defunctionalization is normally performed at an elevated temperature, preferably at the reflux temperature of the solvent employed.
The amine product so formed in Step (b) is then preferably isolated, either in the form of the free base, or in the form of an acid addition salt thereof. Conventional techniques of isolating such free base will be known to one of ordinary skill in the art. Likewise, the acid addition salt of the amine product may also be prepared according to known methods, for example, by treatment of the isolated free base with a conjugate organic acid, such as succinic, tartaric, acetic, citric, maleic, methanesulfonic, or p-toluenesulfonic acid, and the like, or a conjugate inorganic acid, such as hydrochloric, hydrobromic, sulfuric, or nitric acid, and the like. As was previously disclosed hereinabove, facile product isolation and augmented purity are normally best achieved where such salt formation is carried out in a reaction-inert solvent, such as a non-solvent from which the desired salt precipitates upon formation, or in a solvent from which the formed salt precipitates upon subsequent addition of a non-solvent.
In another aspect, the present invention provides the compound of the structural formula 
or an acid addition salt thereof.
In another aspect, the present invention provides the compound of the structural formula 
or an acid addition salt thereof.
In yet another aspect, the present invention provides the compound of the structural formula 
or an acid addition salt thereof.